Expression Pattern of Immunoproteasome Subunits in Human Thymus

The expression pattern of immunoproteasomes in human thymus has not been analyzed but may have important consequences during thymic selection. Here we examined the expression patterns of immunoproteasome subunits in fetal and adult thymic tissues by immunohistochemistry and found that all three subunits are expressed in both cortical and medullary stromal cells. These data suggest that thymic selection in human can be affected by peptide repertoires generated by immunoproteasomes.

Sepsis Mortality in CIITA Deficient Mice is Associated with Excessive Release of High-mobility Group Box 1

BACKGROUND: Down regulation of major histocompatibility complex class II transactivator (CIITA) has been identified as a major factor of immunosuppression in sepsis and the level of CIITA expression inversely correlates with the degree of severity. However, it has not been fully elucidated whether the lower expression of CIITA is a cause of disease process or a just associated sign. Here we determined whether the CIITA deficiency decreased survival rate using murine sepsis model. METHODS: Major histocompatibility complex class II (MHC-II) deficient, CIITA deficient and wild type B6 mice were subjected to cecal ligation puncture (CLP) surgery. CIITA and recombination activation gene (RAG)-1 double deficient mice were generated to test the role of lymphocytes in CIITA-associated sepsis progression. RESULTS: Sepsis mortality was enhanced in CIITA deficient mice, not by impaired bacterial clearance resulted from CD4 T cell depletion, but hyper-inflammatory response such as excessive release of a pro-inflammatory cytokine, high-mobility group box 1 (HMGB1). CONCLUSION: Our results demonstrate that CIITA deficiency affects the course of sepsis via the unexpected function of CIITA, regulation of cytokine release.

Delayed allograft rejection by the suppression of class II transactivator

We examined the effect of class II transactivator (CIITA) down-modulation on allograft rejection. To inhibit the function of CIITA, we constructed a series of CIITA mutants and found one exhibiting the dominant-negative effect on the regulation of major histocompatibility complex (MHC) class II expression. To test whether the CIITA dominant-negative mutant reduces immunogenecity, CIITA-transfected melanoma cells were injected into allogeneic host and assessed for immune evading activity against host immune cells. We demonstrated that the CIITA dominant-negative mutant allowed tumor nodules to develop earlier in the lung than control by this tumor challenge study. Furthermore, skin grafts deficient for CIITA also survived longer than wild-type in allogeneic hosts. Both the tumor challenge and skin graft studies suggest the inhibition of CIITA molecules in donor tissue would be beneficial to the control of allo-response.

CD24 Expression in Gastric Adenocarcinoma Is Associated with Tumor Invasiveness

BACKGROUND: CD24, also referred to as the heat stable antigen in mice, is a glycosyl phosphatidylinositol- linked glycoprotein expressed by thymocytes, B cells, neutrophils and immature neuronal cells. It has been recently observed in a variety of human malignancy. Here, we demonstrated the expression of CD24 in gastric adenocarcinomas. METHODS: A total of 40 gastric adenocarcinomas and 20 tubular adenomas were immunohistochemically examined for the expression of CD24 and matrix metalloproteinase-2 (MMP-2) proteins. The immunoreactivity of CD24 was semiquantitatively scored (0, 1+, 2+) and compared with clinicopathologic variables and MMP-2 expression in tumor cells. RESULTS: CD24 was rarely expressed in normal gastric tissue and not expressed in tubular adenoma. In contrast, a moderate/strong expression (2+) of CD24 was observed in 25% of gastric adenocarcinomas, and 30% cases showed a weak CD24 staining (1+). Moreover, CD24 expression was significantly correlated with the depth of tumor invasion and MMP-2 expression. CONCLUSION: These results suggest that the aberrant expression of CD24 in gastric adenocarcinomas might be associated with tumor progression and invasiveness.

Effect of Atorvastatin, a HMG-CoA Reductase Inhibitor, in Experimental Colitis in Mice

BACKGROUND: The statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are approved for cholesterol reduction, and may also be beneficial in the treatment of inflammatory disease. In this study, atorvastatin was tested in experimental colitis, a disease model of inflammatory bowel disease. METHODS: To induce colitis, dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS) were administrated to C57BL/6 or BALB/c mice. Mice were monitored daily for loss of body weight and survival for indicated days. Colon length and histology were examined after sacrifice. RESULTS: The administration of DSS induced marked colonic inflammation and shortening, and resulted in a loss of body weight. DSSinduced colitis was not affected by atorvastatin treatment, but in contrast, the administration of atorvastatin relieved TNBS-induced colitis with a resultant rapid recovery of weight loss and a reduction in colonic length shortening. Histologically, inflammatory cell infiltration in the colonic wall, mucosal ulceration and crypt disruption were also suppressed in atorvastatin treated mice. CONCLUSION: These results suggest that atorvastatin preserves intestinal integrity in colitis, probably via the modulation of Th cell-mediated immune response, in a manner independent of innate immunity.